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Cationic nanoparticles have superior transvascular flux into solid tumors: insights from a mathematical model.

ABSTRACT: Despite their great promise, only a few nanoparticle formulations have been approved for clinical use in oncology. The failure of nano-scale drugs to enhance cancer therapy is in large part due to inefficient delivery. To overcome this outstanding problem, a better understanding of how the physical properties (i.e., size, surface chemistry, and shape) of nanoparticles affect their transvascular transport in tumors is required. In this study, we developed a mathematical model for nanoparticle delivery to solid tumors taking into account electrostatic interactions between the particles and the negatively-charged pores of the vessel wall. The model predictions suggest that electrostatic repulsion has a minor effect on the transvascular transport of nanoparticles. On the contrary, electrostatic attraction, caused even by small cationic charges (surface charge density less than 3 × 10(-3) C/m(2)) can lead to a twofold or more increase in the transvascular flux of nanoparticles into the tumor interstitial space. Importantly, for every nanoparticle size, there is a value of charge density above which a steep increase in transvascular transport is predicted. Our model provides important guidelines for the optimal design of nanoparticle formulation for delivery to solid tumors.

SUBMITTER: Stylianopoulos T

PROVIDER: S-EPMC3886728 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Cationic nanoparticles have superior transvascular flux into solid tumors: insights from a mathematical model.

Stylianopoulos Triantafyllos T Soteriou Konstantinos K Fukumura Dai D Jain Rakesh K RK

Annals of biomedical engineering 20120802 1

Despite their great promise, only a few nanoparticle formulations have been approved for clinical use in oncology. The failure of nano-scale drugs to enhance cancer therapy is in large part due to inefficient delivery. To overcome this outstanding problem, a better understanding of how the physical properties (i.e., size, surface chemistry, and shape) of nanoparticles affect their transvascular transport in tumors is required. In this study, we developed a mathematical model for nanoparticle del ...[more]

PMID: 22855118

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Project description:IntroductionComputational models yield valuable insights into biological interactions not fully elucidated by experimental approaches. This study investigates an innovative spatiotemporal model for simulating the controlled release and dispersion of radiopharmaceutical therapy (RPT) using 177Lu-PSMA, a prostate-specific membrane antigen (PSMA) targeted radiopharmaceutical, within solid tumors via a dual-release implantable delivery system. Local delivery of anticancer agents presents a strategic approach to mitigate adverse effects while optimizing therapeutic outcomes.MethodsThis study evaluates various factors impacting RPT efficacy, including hypoxia region extension, binding affinity, and initial drug dosage, employing a novel 3-dimensional computational model. Analysis gauges the influence of these factors on radiopharmaceutical agent concentration within the tumor microenvironment. Furthermore, spatial and temporal radiopharmaceutical distribution within both the tumor and surrounding tissue is explored.ResultsAnalysis indicates a significantly higher total concentration area under the curve within the tumor region compared to surrounding normal tissue. Moreover, drug distribution exhibits notably superior efficacy compared to the radiation source. Additionally, low microvascular density in extended hypoxia regions enhances drug availability, facilitating improved binding to PSMA receptors and enhancing therapeutic effectiveness. Reductions in the dissociation constant (KD) lead to heightened binding affinity and increased internalized drug concentration. Evaluation of initial radioactivities (7.1×107, 7.1×108, and 7.1×109 [Bq]) indicates that an activity of 7.1×108 [Bq] offers a favorable balance between tumor cell elimination and minimal impact on normal tissues.DiscussionThese findings underscore the potential of localized radiopharmaceutical delivery strategies and emphasize the crucial role of released drugs relative to the radiation source (implant) in effective tumor treatment. Decreasing the proximity of the drug to the microvascular network and enhancing its distribution within the tumor promote a more effective therapeutic outcome. The study furnishes valuable insights for future experimental investigations and clinical trials, aiming to refine medication protocols and minimize reliance on in vivo testing.

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Project description:The distribution of nanomedicines inside solid tumors is often restricted to perivascular areas, leaving most distal tumor cells out of reach. This partly explains modest patient benefit of many nanomedicines compared to their free-form counterparts. The objective for this study is to develop a mathematical model to quantitatively analyze this phenomenon and the influencing factors to such perivascular distribution and seek for effective strategies to alleviate this. A spatial tumor distribution model was firstly constructed to mimic the geometrical structure of tumor vessels and the surrounding tumor cells. This tumor model was further integrated with a systemic pharmacokinetics model for nanoparticles. A variety of factors on the tumor spatial distributions of nanomedicines were considered in the model. With the model, we quantified the effect of these influencing factors on tumor delivery efficacy (ID %), the magnitude of heterogeneous distribution (H index), and the effect of enhanced permeability and retention (EPR). In particularly, we compared the spatial distributions of the nanoparticles and the free payloads insides tumors. The model predicted high degrees of distributional heterogeneity for both nanoparticles and free payloads. The degree of heterogeneity and the influencing factors for free payloads were markedly different from those for nanoparticles. We found that nanoparticle diffusion coefficient was the most effective factor in reducing the nanoparticle H index but exerted moderate influence on the free payloads H index. The most effective factor in reducing the H index of free payload was payload diffusion coefficient. The factors that improved free payload distribution were closely associated with higher drug efficacy. In contrast, the factors that improved nanoparticle spatial distributions did not always confer improved anti-tumor efficacy of the delivered drug. These findings highlight the importance of assessing the heterogeneous free payload distribution in tumors for the development of effective nanomedicines.

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Cationic nanoparticles have superior transvascular flux into solid tumors: insights from a mathematical model.

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Cationic nanoparticles have superior transvascular flux into solid tumors: insights from a mathematical model.

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